Compounding with capsules
Hard-gelatinous capsules are the oral solid dosage form of choice in compounding pharmacies due to their versatility. Although they are considered a simple dosage form of preparation, their development may pose significant challenges to the formulator, including:
- selection of the right excipient blend required to fill a capsule (containing wetting agents, lubricants, disintegrants, diluents, etc.)
- compatibility issues between the ingredients
- stability
- powder mixing and homogeneity
- powder flowability and lubrication
Besides these common issues, the in vitro dissolution rate of the conveyed active pharmaceutical ingredient (API) is also something that needs to be considered, as it must first be released and dissolved in the gastrointestinal (GI) fluids before being absorbed by the mucosa of the GI tract. Therefore, developing an efficient formulation in the form of capsules should consider pharmaceutical and biopharmaceutical aspects to assist in the careful selection of the excipients.
Enter: The excipients
For a long time, excipients were believed to be pharmacologically inert substances used only for loading, to optimize the processing of the powder-based dosage form, or to facilitate the delivery of the API. However, currently, it is known that, in addition to their traditional functions, the excipients need to play the role of an adjuvant, assisting, for example, the API to promote its activity through influence on the release from the pharmaceutical dosage form.
Defining an excipient blend for hard-shell capsules is not always a straightforward process, and it can be time-consuming, as the pharmacist would need to evaluate the performance via trial and error. When choosing the excipient composition, it is essential to consider its role and several other technical criteria, such as:
- API stability profile
- API-excipient compatibility
- powder flowability and packing
- powder mixing process and its critical factors
- disintegration and dissolution rate
- powder hygroscopicity
- desirable release profile
- patient adherence and tolerance
- API bioavailability profile
Biopharmaceutical Classification System (BCS)
The creation of the Biopharmaceutical Classification System (BCS) provided a crucial step toward the standardization and automatization of the decision process for excipients. The BCS provides the formulator with the ability to assess the contribution that comes from the rate of dissolution, solubility, and intestinal permeability in the oral absorption of an API. It enables the adjustment of dissolution patterns for medications, reduces the need for in vivo bioequivalence testing, and promotes the mechanistic development of dosage forms.
The influence of excipients
Toxicity of ingredients
As an example of the importance of the excipient’s role on dosage-form performance, we can consider an intoxication that occurred in Australia in the late 1960s where epileptic patients taking phenytoin capsules experienced intoxication due to the replacement of the diluent. Calcium sulfate (low solubility in aqueous media, which prolonged the release of the API) was changed by lactose (high solubility in aqueous media, which triggers the immediate release of the API), and this led to an increase in the mean serum concentration of phenytoin (a narrow therapeutic index API) by a factor of 4.5 beyond the toxic threshold.
Slow release
Another remarkable example of the influence of the excipient on the kinetics of API release from this pharmaceutical form is the slow-release capsules. In these capsules, the slow release of the API is due to the presence of one or more excipients that form a hydrophilic matrix, such as hydroxypropyl methylcellulose (HPMC). The slowing of API release promoted by the hydrophilic matrix minimizes the adverse effects associated with the high peak plasma concentrations stimulated by some APIs and APIs being released and absorbed more slowly. In general, the release speed is decreased as the proportion of the matrix polymer increases relative to the water-soluble ingredients that may be present in the formulation. However, it is difficult to predict the exact release profile of an API from these modified-release capsules. This makes it even more important to standardize every step involved in preparing these capsules, including conducting laboratory assessments to determine the dissolution profile of the formulation and continuous monitoring of the patient’s clinical response.
Power loss during the capsule-filling process
The main reasons for the powder adherence are the electrostatic forces generated by powder interparticle friction, a low powder melting point, and the tendency of certain powders to absorb moisture. Additionally, moisture plays a prominent negative role in pharmaceutical preparations, particularly in solid pharmaceutical forms and exceptionally in hard-gelatin capsules, which are known to be sensitive to its presence. The chemical and physical stability of some APIs and the capsule shell itself can be affected by moisture. The hygroscopic nature of excipients and active ingredients should be considered in formulation development. Hygroscopic, deliquescent powders or those with a tendency to absorb moisture should not be mixed with excipients containing large amounts of water such as starch. Absorbent excipients or excipients with low moisture uptake such as microcrystalline cellulose and mannitol should be preferred in this situation.
DiluCap: The right excipient for your capsules
Fagron developed a line of excipients with many studies to guarantee the performance and safety of compounded capsules. DiluCap is a line of excipients specially developed so that the pharmacist can compound every capsule formulation with ease and trust in its final characteristics. All excipients were developed following scientific criteria and were tested to prove their performance. The line is composed of six excipients:
- DiluCap SLD: For Soluble APIs Class I and III (BCS). Promotes the disintegration without a negative impact on dissolution.
- DiluCap PSD: For Poorly soluble APIs Class II and IV (BCS). Favors the disintegration and dissolution of the API.
- DiluCap SR: For APIs requiring modified release (slow release). Reduces the disintegration and release rate of the API, promoting its slow release. Prevents plasma peaks responsible for adverse effects.
- DiluCap Hygro: For hygroscopic or deliquescent APIs. Reduces hygroscopicity, deliquescence, and eutectic mixture formation.
- DiluCap Antioxi: For APIs susceptible to oxidation. Chemical stabilizer. Antioxidant. Reduces water activity, decreasing chemical degradation.
- DiluCap OD: For orodispersible APIs (sprinkle capsules) or candidate APIs for sublingual administration. Promotes transmucosal permeation.
Advantages of DiluCap:
- Avoidance of segregation between API and other formulation components
- Preservation of API stability
- Dose accuracy, as they facilitate the distribution of particles from the API
- Modulation of the solubility and bioavailability of API
- Good flux properties
- Absence of allergens such as lactose, gluten, soy, and others
- Proven functionality
- No need for other adjuvants
- Developed based on the biopharmaceutical classification
- Physiologically inert
- Reduction of process time and the number of items in stock
- Batch-to-batch reproducibility
You can know more about DiluCap here.
